Critical Role of SREBP-1c Large-VLDL Pathway in Environment-Induced Hypertriglyceridemia of Apo AV Deficiency
Critical Role of SREBP-1c Large-VLDL Pathway in Environment-Induced Hypertriglyceridemia of Apo AV Deficiency
复制标题
SREBP-1c 大 VLDL 通路在环境诱发的 Apo AV 缺乏症高甘油三酯血症中的关键作用
DOI：
10.1161/atvbaha.118.311931
复制
发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Okazaki H.
中科院分区：
文献类型：
--
作者：
Takanashi M;Kimura T;Li C;Tanaka M;Matsuhashi A;Yoshida H;Noda A;Xu P;Takase S;Okazaki S;Iizuka Y;Kumagai H;Ikeda Y;Gotoda T;Takahashi M;Yagyu H;Ishibashi S;Yamauchi T;Kadowaki T;Liang G;Okazaki H.
APOA 5变异与高脂血症、心血管疾病和急性胰腺炎风险增加密切相关。载脂蛋白AV功能障碍的高脂血症常受环境因素如高碳水化合物饮食或衰老的影响。迄今为止，这些环境因素诱导高胆固醇血症的分子机制尚不清楚，导致高危高胆固醇血症治疗不足。以前，我们报道了LXR（liver X receptor）-SREBP（sterol regulatory element-binding protein）-1c途径调节LXR激动剂诱导的大极低密度脂蛋白（large-VLDL）的产生。然而，病理生理学的相关性的发现仍然unknow.Approach和ResultsHere，我们重建的环境诱导的hyperglycidemia表型的humanAPOA 5缺陷在Apoa 5 −/−小鼠和描绘的作用SREBP-1c在体内通过generatingApoa 5 −/−;Srebp-1c−/−小鼠。Apoa 5 −/−小鼠在普通饲料喂养时表现出中度高脂血症，在高碳水化合物喂养或衰老时发展为严重的高脂血症，如在人类apo AV缺乏症患者中所见。这些反应在Apoa 5 −/−;Srebp-1c−/−小鼠中几乎完全消失。进一步的机制研究表明，在响应这些环境因素，SREBP-1C被激活，以增加甘油三酯的合成，并允许甘油三酯纳入异常大的极低密度脂蛋白颗粒，这需要载脂蛋白AV有效clearance.ConclusionsSevere hyperglyceridemia的发展只有当遗传因素（载脂蛋白AV缺陷）和环境影响（SREBP-1C激活）共存。我们证明了通过SREBP-1c调节大尺寸VLDL颗粒的产生决定了载脂蛋白AV缺乏症患者的血浆甘油三酯水平。我们的研究结果解释了载脂蛋白AV缺乏的迟发性高脂血症表型的长期谜团，并提出了一种新的方法来治疗高脂血症靶向基因介导的环境效应。
ObjectiveAPOA5variants are strongly associated with hypertriglyceridemia, as well as increased risks of cardiovascular disease and acute pancreatitis. Hypertriglyceridemia in apo AV dysfunction often aggravates by environmental factors such as high-carbohydrate diets or aging. To date, the molecular mechanisms by which these environmental factors induce hypertriglyceridemia are poorly defined, leaving the high-risk hypertriglyceridemia condition undertreated. Previously, we reported that LXR (liver X receptor)-SREBP (sterol regulatory element-binding protein)-1c pathway regulates large-VLDL (very low-density lipoprotein) production induced by LXR agonist. However, the pathophysiological relevance of the finding remains unknown.Approach and ResultsHere, we reconstitute the environment-induced hypertriglyceridemia phenotype of humanAPOA5deficiency inApoa5−/−mice and delineate the role of SREBP-1c in vivo by generatingApoa5−/−;Srebp-1c−/−mice. TheApoa5−/−mice, which showed moderate hypertriglyceridemia on a chow diet, developed severe hypertriglyceridemia on high-carbohydrate feeding or aging as seen in patients with human apo AV deficiency. These responses were nearly completely abolished in theApoa5−/−;Srebp-1c−/−mice. Further mechanistic studies revealed that in response to these environmental factors, SREBP-1c was activated to increase triglyceride synthesis and to permit the incorporation of triglyceride into abnormally large-VLDL particles, which require apo AV for efficient clearance.ConclusionsSevere hypertriglyceridemia develops only when genetic factors (apo AV deficiency) and environmental effects (SREBP-1c activation) coexist. We demonstrate that the regulated production of large-sized VLDL particles via SREBP-1c determines plasma triglyceride levels in apo AV deficiency. Our findings explain the long-standing enigma of the late-onset hypertriglyceridemia phenotype of apo AV deficiency and suggest a new approach to treat hypertriglyceridemia by targeting genes that mediate environmental effects.
登录
查看更多内容
影响因子：
15.9
作者：
Rohlmann, A;Gotthardt, M;Herz, J
通讯作者：
Herz, J
影响因子：
15.9
作者：
REAVEN, GM;CHEN, YDI;KRAUSS, RM
通讯作者：
KRAUSS, RM
影响因子：
7.7
作者：
Matsuzaka, T;Shimano, H;Yamada, N
通讯作者：
Yamada, N
甾醇调节元件结合蛋白 1c 介导胰岛素对肝基因表达的作用。
影响因子：
3.9
作者：
Pascal Ferré;Marc Foretz;Dalila Azzout;D. Bécard;F. Foufelle
通讯作者：
F. Foufelle
影响因子：
29
作者：
Haas JT;Miao J;Chanda D;Wang Y;Zhao E;Haas ME;Hirschey M;Vaitheesvaran B;Farese RV Jr;Kurland IJ;Graham M;Crooke R;Foufelle F;Biddinger SB
通讯作者：
Biddinger SB